Delayed rejection of MHC class II-disparate skin allografts in mice treated with farnesyltransferase inhibitors.
Farnesyltransferase inhibitors (FTIs), developed as anti-cancer drugs, have the potential to modulate immune responses without causing nonspecific immune suppression. We have investigated the possibility that FTIs, by affecting T cell cytokine secretion, can attenuate alloreactive immune responses. The effects of FTIs on murine alloreactive T cells were determined both in vitro, by measuring cytokine secretion or cell proliferation in mixed lymphocyte cultures, and in vivo, by performing skin allografts from H-2(bm12) mice to MHC class II-disparate B6 mice. We found that two different FTIs, ABT-100 and L-744,832, blocked secretion of IFN-gamma, IL-2, IL-4, and TNF-alpha from naïve T cells in vitro. ABT-100 and L-744,832 blocked cytokine production from both CD4(+) and CD8(+) naïve T cells stimulated with CD3 and CD28 antibodies, but only if the cells were pretreated with the FTIs for 48 h. Proliferation of alloreactive T cells in mixed lymphocyte cultures was blocked by either FTI. We also found that the proliferation of enriched T cells stimulated with IL-2 was blocked by ABT-100 treatment. In mice with an MHC class II-disparate skin graft, rejection of primary allografts was significantly delayed by treatment with either ABT-100 or L-744,832. Secondary rejection in mice previously primed to the alloantigen was found to be unaffected by L-744,832 treatment. We have shown that FTIs can block T cell cytokine secretion and attenuate alloreactive immune responses. The ability of FTIs to block secretion of cytokines, including IFN-gamma and IL-4, from naïve T cells provides a likely biological mechanism for the specific suppression of class II MHC-mediated allorejection. These results demonstrate that FTIs may have useful immunomodulatory activity due to their ability to delay priming to alloantigens.
Gaylo
Alison E
AE
Cell Biology/Biochemistry Program, Biology Department, Bucknell University, Lewisburg, PA 17837, United States.
Laux
Kathleen S
KS
Batzel
Erika J
EJ
Berg
Morgan E
ME
Field
Kenneth A
KA
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects*
C503142:ABT-100; D016207:Cytokines; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D007093:Imidazoles; D051231:Farnesyltranstransferase